In FY08 we studied the pathogenic process involved in prion/TSE diseases by using mice genetically deficient in a chemokine receptor gene, CCR1. These mice succumbed more rapidly than wild-type (WT) mice following scrapie infection, but the levels of the disease-associated protease-resistant PrP were paradoxically lower in CCR1 knockout (KO) mice. Infected KO mice had upregulation of CCL3, a CCR1 ligand, and CCR5, a receptor with specificity for CCL3. Both infected KO and WT mice had upregulation of CCR5-mediated signaling involving activation of Erk1/2 in astrocytes; however, activation was earlier in KO mice suggesting a role in pathogenesis. In both mouse strains activation of the Erk1/2 pathway may lead to astrocyte dysfunction resulting in neurodegeneration.